Transcript Mechanisms and Treatment of Multidrug Resistant (MDR) Gram

Building Stewardship:
A Team Approach
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Appropriate initial
antibiotic while improving
patient outcomes and
heathcare
Unnecessary
antibiotics and adverse
patient outcomes and
increased cost
A Balancing Act
Empiric
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Initial administration of a broad-spectrum antibiotic regimen
that attempts to improve outcomes and minimize resistance.
Defined or Targeted
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Modification of antimicrobial therapy once the cause of
infection is identified. Therapy may also be discontinued if the
diagnosis of infection becomes unlikely.1
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Focus on de-escalation of antibiotic therapy with the goal of
minimizing resistance and toxicity, and improving costeffectiveness.2,3
1. Kollef MH. Drugs. 2003;63:2157–2168.
2. Kollef MH. Crit Care Med. 2001;29:1473–1475.
3. Evans RS et al. N Engl J Med. 1998;338:232–238.
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Enterococcus
S. aureus
Klebsiella spp.
Acinetobacter
P. aeruginosa
Enterobacter spp.
Boucher H, et al, Clin Infect Dis 2009;48:1-12
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Antimicrobial stewardship involves the optimal
selection, dose and duration of an antibiotic
resulting in the cure or prevention of infection
with minimal unintended consequences to the
patient including emergence of resistance,
adverse drug events, and cost.
Ultimate goal is improved patient care and
healthcare outcomes
Dellit TH, et al. CID 2007;44:159-77,
Hand K, et al. Hospital Pharmacist 2004;11:459-64
Paskovaty A, et al IJAA 2005;25:1-10
Simonsen GS, et al Bull WHO 2004;82:928-34
Simonsen GS, et al . Bull WHO 2004;82:928-34
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Promoting optimal antimicrobial use
Reducing the transmission of infections
Antimicrobial Resistance: Patients and hospitals in
Peril
 The Clinical Consequences of Antimicrobial
Resistance
 Transmission Control to Prevent the Spread of
MDROs in Health Care Facilities
 Antimicrobial Stewardship
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Joint Commission Resources 2009
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Infectious Diseases
Specialists
Infection Control
Administration
Clinical
Pharmacists
Antimicrobial
Control
OR Personnel
Nursing
Surgical Infection
Experts/Surgeons
Microbiology
Pulmonary/
Intensivist
 Prospective audit with intervention and feedback
 Formulary restriction and preauthorization
Supplemental Strategies
 Education, guidelines, clinical pathways
 Dose optimization via PK-PD
 De-escalation/Streamlining
 Antimicrobial order forms/order sets if CPOE
 IV-PO switch
 Computerized decision support
 Others
Dellit TH, et al. CID 2007;44:159-77
Hand K, et al Hospital Pharmacist 2004;11:459-64
Paskovaty A, et al IJAA 2005;25:1-10
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Prospective audit
system
 Stewardship program
 Outcomes
▪ Reason for treatment,
cultures, empirical, and
de-escalation
▪ LOS, mortality, and
% interventions
accepted
IV to Oral interchange
Toth NR, et al Am J Health-Syst Pharm 2010;67:747-9
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Sentri7
SafetySurveillor
TheraDoc
Computerized physician order entry
Benchmarking and local antimicrobials point
prevalence surveys (state may consider doing
this)
Claridge JA, et al. Surg Infect 2010;11:125-31
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Lancaster JW, et al. Pharmacotherapy 2008;28(7):852-62
Antimicrobial therapy of established infection
should be limited to 4–7 days, unless it is difficult to
achieve adequate source control
 Bowel injuries due to penetrating, blunt, or
iatrogenic trauma repaired within 12 h and any
other intraoperative contamination of the operative
field by enteric contents should be treated with
antibiotics for <24 hours
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Lack of evidence of infections includes, being afebrile, have normal WBC,
and tolerating an oral diet.
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Biomarkers
 Procalcitonin
 CRP
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PNA FISH
PCR
E-test of patient samples
Lawrence KL, et al. Am J Respir Crit Care Med 2009;198:434-8
Cals JWL, et al. Ann Fam Med 2010;8:124-33
Schuetz R, et al. JAMA 2009;302:1059-66
Bouza E, et al CID 2007;44:382-7
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Antimicrobial usage
 Days of therapy
 Appropriateness of treatment
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Antimicrobial cost
Bacterial susceptibilities
Patient outcomes
Antimicrobial adverse events
Acceptance of recommendations
Prescribers surveys
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Provide advice on some of the practical
aspects of starting a new stewardship program
or expanding an existing program, with special
commentary regarding the unique challenges
facing community and teaching institutions.
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The members of the team have to fit the
personal available
 Staff physician with ID interest
 P&T chair or committee member
 Hospitalist with interest in ID
 Non–ID-trained clinical pharmacist
 Staff pharmacists (with certification in stewardship)
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Performing selected stewardship activities
should be considered successful
 Helping patients is the goal, not struggling to follow
guidelines at the expensive to a successful program
for your institution
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Lines of authority and reporting are key
 Quality and Safety
 P&T for assistance with P&P and protocol approval
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Outcome Metrics
 CMS outcomes (CABP and SCIP)
 Percentage of appropriate IV to PO
 Point prevalence of antimicrobial use
 Percent of appropriate antimicrobial regimens
 Percent of patients with VAP or ABSSTI treat according to
protocol (antimicrobial and non-antimicrobial metrics)
 Antibiogram changes over time
 Process Metrics
 Percent of recommendations accepted (numbers and type)
 CMS outcomes
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Challenges faced by Community Hospitals
 Lack of sufficient resources
▪ Private ID or NO ID physicians (or those that do not
want to be involved)
▪ ID pharmacist
▪ No extra staff (especially pharmacy)
▪ On site laboratory for C&S data
▪ Antibiograms which include non-formulary agents
▪ No IT systems for data gathering or analysis
▪ Dealing with non-compliant prescribers
▪ Embrace use of non-traditional stewardship personnel
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One the program is approved the following should be
determined
 What activities will be performed?
 By which person?
 How frequently?
 With what authority?
 What is the time line for reporting the data?
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Advertise, market and educate direct care providers about the
programs (think grass roots politics)
Notify clinicians about changes that impact the program
Report program successes and failures
Share data with individual prescribers /departments when
possible
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Provide descriptors of antimicrobial activity profiles
Provide surrogate markers to predict drug activity
Integrate “bug” and “drug” data
Antimicrobial
PK/PD
Host
Pathogen
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β-lactams
 “not much happens until an adequate proportion
of PBP are occupied”
 Smaller doses, more frequently
 Prolonged or continuous infusion
 Time>MIC
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Aminoglycosides/Fluoroquinolones
 AUC:MIC
 Cmax/MIC
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Dose AND MIC matter
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β-lactams (stasis and near maximal killing)
 Cephalosporins: 35% and 65%
 Carbapenems: 20% and 40%
 Penicillins: 30% and 50%
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Fluoroquinolones (stasis and near maximal killing)
 AUC/MIC: 20-25 and 250-300
 Ambrose et al in CABP: 30 needed for clinical cure
 HAP/VAP: AUC/MIC for levofloxacin 87 need for micro cure
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Best represented by
Time>MIC
 Optimal Time>MIC
varies
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Concentration
 Usually at least 40% of
dosing interval
 >50% in neutropenia
Time>MIC
MIC
Time
Best represented by
Cmax:MIC ratio
 Cmax:MIC ratio >8-12
associated with clinical
success
 Optimal ratio varies
with drug and
organism
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Concentration
Cmax:MIC
MIC
Time
80mg/kg q24h
40mg/kg q12h
20mg/kg q6h
Control
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Dose-fractionation experiment with lomefloxacin in an animal model
Same total dose given as different regimens
Lode, et al. Clin Inf Dis 1998;27:33-9
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Varies by particular isolate of organism
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 “Same drug, different bug”
Ex. Ciprofloxacin vs. Pseudomonas
Cipro-resistant
Cipro-sensitive
Concentration
AUC/
MIC
AUC/
MIC
MIC<1 mcg/mL
Time
MIC
MIC=4 mcg/mL
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Traditional pharmacokinetic parameter
Calculated based on total serum
concentrations of drug
 Obtained by sampling at multiple time points and
integrating under curve
Concentration
Time
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Surrogate for AUC of unbound drug at site of
infection…at receptor site
Effective
Assayed
Protein Binding
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Entry into infected site
Access to bacterial target
Does not account for susceptibility
of organism
Difficult to measure in clinical practice
Random
pharmacokinetics
and MIC values
from dataset
AUC
MIC
Calculate
pharmacodynamic
parameter
Plot results in
a probability chart
AUC:MIC
Dudley & Ambrose. Curr Opin Microbiol 2000;3:515−521
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Monte Carlo simulation
 determine distribution of antimicrobial potency
(eg MIC distribution)
 determine distribution of antimicrobial exposures
(eg AUCs)
 computer program randomly selects parameters from
each of the distributions (500, 5000… iterations =
patients) and the probability distribution of achieving
the preset level (pharmacodynamic target attainment =
specific AUC:MIC or T>MIC) is computed
Nicolau & Ambrose. Am J Med 2001;111(9A):13S–18S
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May be a better surrogate marker of activity than drug
exposure (AUC) or MIC alone
Studies have shown AUC/MIC to be predictive of antimicrobial
activity
Probability of
developing resistance
during treatment for
nosocomial pneumonia
Thomas, et al. Antimicrob Agents Chemo 1998;42:521-7.
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Gram-positive anaerobic bacteria
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Exotoxin producing
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Fecal-oral transmission
 C. difficile infection (CDI) onset median 2-3 days
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Most common cause of infectious diarrhea
 20-30% of antibiotic-associated diarrhea
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
2. Centers for Disease Control and Prevention
1. Ingestion
of spores transmitted
from other patients
via the hands of healthcare
personnel and environment
3. Altered lower intestine flora
(due to antimicrobial use) allows
proliferation of
C. difficile in colon
2. Germination into
growing (vegetative)
form
Sunenshine et al. Cleve Clin J Med. 2006;73:187-97.
4. Toxin A & B Production
leads to colon damage
+/- pseudomembrane
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Age
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Hospital duration
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Antibiotic usage
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Chemotherapy
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Gastrointestinal disruption
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
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Diarrhea
 3 or more unformed stools
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Positive stool test
 Enzyme immunoassay vs. polymerase chain
reaction
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Pseudomembranous colitis
 Colonoscopic or histopathologic findings
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
Clinical definition
Supportive clinical data
Mild or moderate
WBC less than 15,000 AND SCr less
than 1.5 times premorbid level
WBC greater than 15,000 OR SCr
greater than 1.5 times premorbid
level
Severe
Severe, complicated Hypotension, shock, ileus, megacolon
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
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Discontinue any potential causative agent
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Immediately initiate empirical treatment
 Severe or complicated
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Data of probiotic usage is inconclusive
 Not recommended for primary prophylaxis
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
Initial Episodes
Mild or moderate
Recommended Treatment
Metronidazole 500 mg PO
TID for 10-14 days
Severe
Vancomycin 125 mg PO QID
for 10-14 days
Severe, complicated
Vancomycin 500 mg PO QID
plus metronidazole 500 mg
IV Q8H
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
Recurrent Infection
Recommended
Treatment
First recurrence
Second recurrence
Same as initial episode
Vancomycin tapered
and/or pulsed
1. Infect Control Hosp Epidemiol. 2010; 31(5): 431-55.
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Prospective, randomized, double-blind,
placebo- controlled trial
 150 patients completed study
 Stratified patients: mild or severe
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Compared metronidazole 250 mg PO QID to
vancomycin 125 mg PO QID for 10 days
3. Clinic Infect Dis. 2007; 45:302-7.
3. Clinic Infect Dis. 2007; 45:302-7.
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Treatment failures with both metronidazole
and vancomycin
Increasing rates of recurrence with both
vancomycin and metronidazole
Risk of VRE colonization with both agents
ADRs with current treatments especially,
metronidazole
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Macrocycles, a new class of antibacterials for oral
administration
Bactericidal against C. difficile, with a PAE of 6-10 hrs
Inhibits RNA synthesis by RNA polymerases
Fecal concentration are 5000 times the MIC90 of C difficile
isolates
Preservation of the microbiota of the GI tract compared with
vancomycin
Minimal systemic absorption measured in the ng/ml range
Food does increase systemic absorption but increased serum
concentration is NOT clinically significant
Clinical resistance has been observed in the lab and in one
treated patient (MIC from 0.06 to 6 mcg/ml)
Louie T, et al. AAC 2009;53:223-28
Product Label Dificid 2011
NEJM 2011; 364: 422-61
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Inclusion Criteria:
 Adult patients (> 16 y.o.) with a diagnosis of C. difficile
infection
▪ Presence of diarrhea: a change in bowel habits, > 3 unformed bowel
movements in the 24-hour period before randomization
▪ C dif. Toxin A, B, or both in a stool specimen obtained 48 hours
before randomization
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Exclusion Criteria:
 Received: oral bacitracin, fusidic acid, or rifaximin
 Life-threatening of fulminant C. dif infection, toxic
megacolon, previous exposure to fidaxomicin, a history of
ulcerative colitis or Crohn’s disease, or > 1 occurrence of C.
difficile infection within 3 months before the start of the
study were excluded
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Clinical Cure: resolution of diarrhea with maintenance of
resolution for duration of therapy and no further Rx
Clinical failure: persistence of diarrhea, need for additional Rx,
or both
Global cure: resolution of diarrhea without recurrence
Clinical recurrence: If subjects remained in study and had a
follow up assessment at day 36-40, after randomization they
were evaluated for recurrence. Defined as reappearance of
diarrhea within 4 weeks after stopping study medication, +
toxin assay, and need for treatment
Subgroup
MITT Fidax
MITT
Vanco
PP
Fidax
PP
Vanco
Age ≥ 65 years
103/122 (84.4)
131/152 (86.2)
99/113 (87.6)
122/138 (88.4)
Inpatient
136/167 (81.4)
146/187 (78.1)
128/146 (87.7)
136/162 (84)
No Previous
episode of CDI
211/239 (88.3)
217/255 (85.1)
203/222 (91.4)
209/235 (88.9)
NAP1/BI/027
59/75 (78.7)
7/83 (80.7)
56/65 (86.2)
61/72 (84.7)
Non
NAP1/BI/027
117/125 (93.6)
121/132 (91.7)
115/119 (96.6)
119/126 (94.4)
Concurrent
Systemic ABX
67/83 (80.7)
72/94 (76.6)
63/71 (88.7)
67/80 (83.8)
Moderate CDI
102/111 (91.9)
88/106 (83)
99/105 (94.3)
84/97 (86.6)
Severe CDI
92/112 (82.1)
109/123 (88.6)
89/101 (88.1)
107/115 (93)
No differences between the groups were significant
Number/total number (percent)
Subgroup
MITT Fidax
MITT
Vanco
P value
PP
Fidax
PP
Vanco
P
value
Age ≥ 65
years
20/103 19)
40/131
(30.5)
0.05
16/85 (19)
31/103 (30)
0.08
Inpatient
24/136 18)
40/146 (27)
0.05
19/106 (18) 29/111 (26)
0.15
No Previous
episode of
CDI
30/211 (14) 52/217 (24)
0.01
22/175 (13) 41/183 (22)
0.02
NAP1/BI/027
16/59 (27)
14/67 (21)
0.42
11/45 (24)
13/55 (24)
0.93
Non
NAP1/BI/027
12/117 10)
34/121 (28)
<0.001
8/103 (8)
27/106
(25.5)
<0.001
Concurrent
Systemic ABX
14/81 (17)
5/90 (28)
0.10
8/56 (14)
20/65 (31)
0.03
Mild CDI
7/59 (12)
20/68 (29)
0.02
4/44 (9)
13/55 (24)
0.06
Severe CDI
12/92(13)
29/109 (27)
0.02
9/77 (12)
22/95 (23
0.05
Number/total number (percent)
Commercially available test in the world to detect and differentiate
the epidemic strain of C. difficile (027/NAP1/BI).
• With rapid and accurate identification of epidemic strain,
Infection Control professional can stay ahead of potential
outbreak situation.
Innovative multiplex design enables detection of C. difficile
Infection (CDI) and 027/NAP1/BI strain call-out in a single
cartridge
• Cepheid’s Xpert C. difficile/Epi is a real time PCR test that runs on
the GeneXpert system
• GeneXpert system is the first to fully automate and integrate all
the steps required for PCR-based DNA testing: sample
preparation, DNA amplification and detection
Vancomycin PO capsules 125 mg Q6h x 10 days
▪ Red book AWP $31.82 per capsule
▪ $1275 per course
▪ Inpatient, a vancomycin slurry is made by pharmacy for
treatment of CDI
▪ Outpatient, capsules are dispensed and covered by payors
▪ Patient assistance program for PO Vancomycin
 Metronidazole 500 mg PO Q8h x 10 days
▪ Red book AWP $1.38
▪ $41.40 per course
 Fidaxomicin 200 mg PO Q12h x 10 days
▪ Reported cost of $2800
CLSI M100-S19 (2009)
Agent
CLSI M100-S20 (2010)
Susc
Interm
Resis
Susc
Interm
Resis
Cefazolin
≤8
16
≥32
≤1
2
≥4
Cefotaxime
≤8
16-32
≥64
≤1
2
≥4
Ceftizoxime
≤8
16-32
≥64
≤1
2
≥4
Ceftriaxone
≤8
16-32
≥64
≤1
2
≥4
Ceftazidime
≤8
16
≥32
≤1
8
≥16
Aztreonam
≤8
16
≥32
≤1
8
≥16
CLSI M100-S20, 2010
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Why the changes?
 Better PKPD data and knowledge about resistance
mechanism especially ESBLs ± AmpC
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What were they based upon?
 Mostly PD, expert opinion and a few case series.
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How does the change impact treatment?
 May use any agent based on the observed MIC result
and pts factors, carbapenem are not always needed
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How does it impact reporting of ESBL?
 Susceptibility of cephalosporins should NOT be
changed if identified as an ESBLs
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Some ESBL producing isolates are susceptible invitro
 Poor outcomes in patients with infections due to
ESBLs cephs
 Bacteria often have ESBLs and AmpC-like enzymes
 No need for ESBL testing or confirmatory test with
new breakpoints.
 Hospitals using FDA-approved AST devices can
utilize existing FDA interpretive breakpoints
 Either FDA or CLSI susceptibility interpretive
breakpoints are acceptable to accrediting bodies.
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Drug
Susceptible
Doripenem
≤1
Interm
2
Resistance
≥4
Ertapenem
≤ 0.25
0.5
≥1
Imipenem
≤1
2
≥4
Meropenem
≤1
2
≥4
CLSI Meeting Minutes Jan 2009
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